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Publication Open Access Multifunctional alginate-based hydrogel with reversible crosslinking for controlled therapeutics delivery(Elsevier, 2020) Ekinci, Duygu; N/A; Department of Chemical and Biological Engineering; Batool, Syeda Rubab; Nazeer, Muhammad Anwaar; Kızılel, Seda; Şahin, Afsun; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; School of Medicine; N/A; N/A; 28376; 171267Glycan-based alginate hydrogels have great potential in creating new vehicles with responsive behavior and tunable properties for biomedicine. However, precise control and tunability in properties present major barrier for clinical translation of these materials. Here, we report the synthesis of pH responsive anthracene modified glycan-based hydrogels for selective release of therapeutic molecules. Hydrogels were crosslinked through simultaneous photopolymerization of vinyl groups and photodimerization of anthracene. Incorporation of anthracene into these gels leads to reversible control on crosslinking and transition between gel/sol states through dimerization/dedimerization of anthracene groups. Chemotherapeutic drug doxorubicin-loaded hydrogels were then tested in a cancer mimetic microenvironment where 85% of the drug was released from anthracene-conjugated hydrogels at pH 2 for 6 days. Control on gelation with anthracene incorporation was observed through alterations in modulus, where storage modulus was increased two-fold with anthracene conjugation during photopolymerization and photodimerization. Furthermore, cell survival analysis revealed that anthracene conjugation could selectively compromise cancer cell viability without inducing significant toxicity on healthy fibroblasts. This study combines light-induced control of crosslink density due to anthracene and pH-triggered therapeutics delivery with alginate. The approach would be applicable for systems where multiple control is required with high precision.Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access TRMU-related transient liver failure of infancy presents with microcephaly and neurodevelopmental delay(Nature Publishing Group (NPG), 2019) N/A; N/A; Azaklı, Hülya; Börklü Yücel, Esra; Arıkan, Çiğdem; Armutlu, Ayşe; Eraslan, Serpil; Kayserili, Hülya; PhD Student; Faculty Member; Teaching Faculty; Researcher; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; 7945Publication Open Access The structural basis of Akt PH domain interaction with calmodulin(Elsevier, 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a beta-strand rather than an alpha-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3K alpha activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.Publication Open Access Effectiveness of posterior structures in the development of proximal junctional kyphosis following posterior instrumentation: a biomechanical study in a sheep spine model(Elsevier, 2019) Akgül, Turgut; Sarıyılmaz, Kerim; Özkunt, Okan; Dikici, Fatih; Yazıcıoğlu, Önder; N/A; Korkmaz, Murat; Doctor; School of MedicineIntroduction: proximal junctional kyphosis – PJK has been defined by a 10 or greater increase in kyphosis at the proximal junction as measured by the Cobb angle from the caudal endplate of the uppermost instrumented vertebrae (UIV) to the cephalad endplate of the vertebrae 1 segments cranial to the UIV. In this biomechanical study, it is aimed to evaluate effects of interspinosus ligament complex distruption and facet joint degeneration on PJK development. Materials and methods: posterior instrumentation applied between T2 – T7 vertebrae using pedicle screws to randomly selected 21 sheeps, divided into 3 groups. First group selected as control group (CG), of which posterior soft tissue and facet joints are protected. In second group (spinosus group, SG) interspinosus ligament complex which 1 segment cranial to UIV has been transected, and third group (faset group-FG) was applied facet joint excision. 25 N, 50 N, 100 N, 150 N and 200 N forces applied at frequency of 5 Hertz as 100 cycles axial to the samples. Then, 250 N, 275 N and 300 N forces applied static axially. Interspinosus distance, kyphosis angle and discus heights was measured in radiological evaluation. Abnormal PJK was defined by a proximal junctional angle greater than 100 and at least 100 greater than the corresponding preoperative measurement. Results: in CG group, average interspinosus distance was 6,6 ± 1.54 mm and kyphosis angle was 2,2 ± 0.46° before biomechanical testing, and they were measured as 9,4 ± 1.21 mm and 3,3 ±0.44° respectively after forces applied to samples. In SG group, average interspinosus distance was 6,2 ± 1.72 mm and kyphosis angle was 2,7 ± 1.01° before experiment, and they were measured as 20,8 ± 5.66 mm and 15,1 ± 2.34° respectively after forces applied to samples. In FG group, average interspinosus distance was 4,8 ± 1.15 mm and kyphosis angle was −1 ± 4.14° before experiment, and they were measured as 11,1 ±1.96mm and 11 ± 2.87° respectively after forces applied to samples. In comparison to group CG, statistically significant junctional kyphosis was seen on both FG and SG group after statistical analysis. (p < 0.05). PJK was seen statistically significant more on SG group than FG group. (p < 0.05). Not any statistically significant difference was seen on measurement of disk distances among three groups. (p > 0.05) Conclusions: protecting interspinosus ligament complex and facet joint unity during posterior surgical treatment for spine deformation is vital to prevent PJK development. Based on our literature review, this is the first biomechanical study that reveals interspinosus ligament complex are more effective on preventing PJK development than facet joints.Publication Open Access Increased hemoglobin oxygen affinity with 5-hydroxymethylfurfural supports cardiac function during severe hypoxia(Frontiers, 2019) Lucas, Alfredo; Ao-ieong, Eilleen S. Y.; Williams, Alexander T.; Jani, Vivek P.; Muller, Cynthia R; Cabrales, Pedro; N/A; Yalçın, Özlem; Researcher; School of Medicine; 218440Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O2) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O2 affinity and Hb-O2 saturation. These products are a counter intuitive therapeutic strategy to increase O2 delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O2 affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O2, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O2 affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O2 delivery during hypoxic hypoxia.Publication Open Access Management of hypoglycemia in newborn: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report(Turkish Pediatric Association, 2019) Aliefendioğlu, Didem; Çoban, Asuman; Hatipoğlu, Nihal; Ecevit, Ayşe; Arısoy, Ayşe Engin; Baş, Firdevs; Bideci, Aysun; Özek, Eren; N/A; Yeşiltepe Mutlu, Rahime Gül; Faculty Member; School of Medicine; 153511Hypoglycemia is one of the most important and most common metabolic problems of the newborn because it poses a risk of neurological injury, if it is prolonged and recurs. Therefore, newborns who carry a risk of hypoglycemia should be fed immediately after delivery and the blood glucose level should be measured with intervals of 2-3 hours from the 30th minute alter feeding. The threshold value for hypoglycemia is 40 mg/dL for the first 24 hours in symptomatic babies. In asymptomatic babies, this value is considered 25 mg/dL for 0-4 hours, 35 mg/dl for 4-24 hours, 50 mg/dL alter 24 hours and 60 mg/dL after 48 hours. Screening should be performed with bed-side test sticks. When values near the limit value are obtained, confirmation with laboratory method should be done and treatment should be initiated, if necessary. The level targeted with treatment is considered 50 mg/dL in the postnatal first 48 hours before feeding, 60 mg/dL after 48 hours in babies with high risk and above 70 mg/dL in babies with permanent hypoglycemia. In cases in which the blood glucose level is below the threshold value and can not be increased by feeding, a glucose infusion of 6-8 mg/kg/min should be initiated. If symptoms accompany, a mini bolus of 10% dextrose (2 ml/kg/min) should accompany. Incements (2 mg/kg/min) should be performed, if the target level can not be achieved and decrements (2 ml/kg/min) should be performed, if nutrition and stabilization is provided. The infusion should be discontinued, if the infusion rate decreases to 3-5 mg/kg/min. If necessary, blood samples should be obtained during hypoglycemia in terms of differential diagnosis and the investigation should be performed following a 6-hour fasting period in babies fed enterally and at any time when the plasma glucose is <50 mg/dL in babies receiving parenteral infusion. The hypoglycemic babies in the risk group whose infusions have been terminated can be discharged, if the plasma glucose level is found to be at the target level for two times before feeding and babies with permanent, severe or resistant hypoglycemia can be discharged, if the plasma glucose level is >60 mg/dL following a 6-hour fast. / Hipoglisemi, uzun sürmesi ve tekrarlaması durumunda nörolojik zedelenme riski nedeniyle, yenidoğanın en önemli ve en sık metabolik sorunlarından birisidir. Bu nedenle, hipoglisemi riski taşıyan yenidoğanlar, doğum sonrası hemen beslenmeli ve beslenme sonrası 30. dakikadan itibaren 2-3 saat aralıklarla kan glukozuna bakılmalıdır. Hipoglisemi eşik değerleri, ilk 24 saat için belirtisi olanlarda 40 mg/dL, belirtisiz olanlarda 0 - 4 saatte 25 mg/dL, 4-24 saat aralığında 35 mg/dL, 24 saatten sonra 50 mg/ dL, 48 saatten sonra ise 60 mg/dL olarak kabul edilebilir. Tarama hastabaşı test çubukları ile yapılmalı, sınıra yakın değerlerde, laboratuvar yöntemi ile doğrulama yapılırken, gerekliyse tedavi başlanmalıdır. Tedavi ile ulaşılması hedeflenen düzeyler, beslenme öncesi postnatal ilk 48 saatte 50 mg/dL, 48 saatten sonra riskli olanlarda 60 mg/dL, kalıcı hipoglisemili olgularda ise 70 mg/dL’nin üstü olarak kabul edilebilir. Kan glukozu eşik değerin altında olan ve beslenme ile yükseltilemeyen durumlarda, 6-8 mg/kg/dk glukoz infüzyonu başlanmalı, belirti eşlik etmesi durumunda ise 2 ml/kg %10 dekstroz minibolus eşlik etmelidir. Hedef düzeye ulaşılamaması durumunda artışlar ve beslenme ile stabilizasyonun sağlanması durumunda azaltmalar 2 mg/kg/dk olarak yapılmalı, infüzyon hızının 3-5 mg/kg/dk’ye inmesi durumunda ise infüzyon sonlandırılmalıdır. Gerekliyse ayırıcı tanı açısından kan örnekleri hipoglisemi sırasında alınmalı ve araştırma, enteral beslenen bebeklerde 6 saatlik beslenmeme periyodu sonrasında, parenteral infüzyon alanlarda ise plazma glukozunun 60 mg/dL olması durumunda taburcu edilebilirler.Publication Open Access Isolated omental metastasis of renal cell carcinoma after extraperitoneal open partial nephrectomy : a case report(Elsevier, 2016) Sağlıcan, Yeşim; N/A; N/A; N/A; N/A; Acar, Ömer; Sağ, Alan Alper; Falay, Fikri Okan; Selçukbiricik, Fatih; Tabak, Levent; Esen, Tarık; Faculty Member; Faculty Member; Teaching Faculty; Faculty Member; Faculty Member; Faculty Member; School of Medicine; 237530; N/A; N/A; N/A; N/A; N/A; 50536INTRODUCTION: Metachronous metastatic spread of clinically localized renal cell carcinoma (RCC) affects almost 1/3 of the patients. They occur most frequently in lung, liver, bone and brain. Isolated omental metastasis of RCC has not been reported so far. CASE PRESENTATION: A 62-year-old patient previously diagnosed and treated due to pulmonary sarcoidosis has developed an omental metastatic lesion 13 years after having undergone open extraperitoneal partial nephrectomy for T1 clear-cell RCC. Constitutional symptoms and imaging findings that were attributed to the presence of a sarcomatoid paraneoplastic syndrome triggered by the development this metastatic focus complicated the diagnostic work-up. Biopsy of the [18F]-fluorodeoxyglucose (+) lesions confirmed the diagnosis of metastatic RCC and the patient was managed by the resection of the omental mass via near-total omentectomy followed by targeted therapy with a tyrosine kinase inhibitor. DISCUSSION: Late recurrence of RCC has been reported to occur in 10-20% of the patients within 20 years. Therefore lifelong follow up of RCC has been advocated by some authors. Diffuse peritoneal metastases have been reported in certain RCC subtypes with adverse histopathological features. However, isolated omental metastasis without any sign of peritoneal involvement is an extremely rare condition. CONCLUSION: To our knowledge, this is the first reported case of metachronously developed, isolated omental metastasis of an initially T1 clear-cell RCC. Constitutional symptoms, despite a long interval since nephrectomy, should raise the possibility of a paraneoplastic syndrome being associated with metastatic RCC. Morphological and molecular imaging studies together with histopathological documentation will be diagnosticPublication Open Access Improving CO2 separation performance of MIL-53(Al) by incorporating 1-N-Butyl-3-methylimidazolium methyl sulfate(Wiley, 2019) Department of Chemical and Biological Engineering; N/A; Kulak, Harun; Polat, Hüsamettin Mert; Kavak, Safiyye; Keskin, Seda; Uzun, Alper; Faculty Member; Department of Chemical and Biological Engineering; Koç University Tüpraş Energy Center (KUTEM) / Koç Üniversitesi Tüpraş Enerji Merkezi (KÜTEM); Koç University Surface Science and Technology Center (KUYTAM) / Koç Üniversitesi Yüzey Teknolojileri Araştırmaları Merkezi (KUYTAM); Graduate School of Sciences and Engineering; N/A; N/A; N/A; 40548; 599171-n-Butyl-3-methylimidazolium methyl sulfate is incorporated into MIL-53(Al). Detailed characterization is done by X-ray fluorescence, Brunauer-Emmett-Teller surface area, scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Results show that ionic liquid (IL) interacts directly with the framework, significantly modifying the electronic environment of MIL-53(Al). Based on the volumetric gas adsorption measurements, CO2, CH4, and N-2 adsorption capacities decreased from 112.0, 46.4, and 19.6 cc (STP) g(MIL-53(Al))(-1) to 42.2, 13.0, and 4.3 cc (STP) g(MIL-53(Al))(-1) at 5 bar, respectively, upon IL incorporation. Data show that this postsynthesis modification leads to more than two and threefold increase in the ideal selectivity for CO2 over CH4 and N-2 separations, respectively, as compared with pristine MIL-53(Al). The isosteric heat of adsorption (Qst) values show that IL incorporation increases CO2 affinity and decreases CH4 and N-2 affinities. Cycling adsorption-desorption measurements show that the composite could be regenerated with almost no decrease in the CO2 adsorption capacity for six cycles and confirm the lack of any significant IL leaching. The results offer MIL-53(Al) as an excellent platform for the development of a new class of IL/MOF composites with exceptional performance for CO2 separation.Publication Open Access Engineering human stellate cells for beta cell replacement therapy promotes in vivo recruitment of regulatory T cells(Elsevier, 2019) N/A; Department of Chemical and Biological Engineering; Oran, Dilem Ceren; Lokumcu, Tolga; Bal, Tuğba; İnceoğlu, Yasemin; Albayrak, Özgür; Erkan, Murat Mert; Kurtoğlu, Metin; Can, Füsun; Önder, Tuğba Bağcı; Kızılel, Seda; Akolpoğlu, Mükrime Birgül; Faculty Member; Faculty Member; Master Student; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; Graduate School of Health Sciences; College of Engineering; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 103165; 184359; 28376; N/AType 1 diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β cells. One of the promising therapeutic approaches in T1D is the transplantation of islets; however, it has serious limitations. To address these limitations, immunotherapeutic strategies have focused on restoring immunologic tolerance, preventing transplanted cell destruction by patients’ own immune system. Macrophage-derived chemokines such as chemokine-ligand-22 (CCL22) can be utilized for regulatory T cell (Treg) recruitment and graft tolerance. Stellate cells (SCs) have various immunomodulatory functions: recruitment of Tregs and induction of T-cell apoptosis. Here, we designed a unique immune-privileged microenvironment around implantable islets through overexpression of CCL22 proteins by SCs. We prepared pseudoislets with insulin-secreting mouse insulinoma-6 (MIN6) cells and human SCs as a model to mimic naive islet morphology. Our results demonstrated that transduced SCs can secrete CCL22 and recruit Tregs toward the implantation site in vivo. This study is promising to provide a fundamental understanding of SC-islet interaction and ligand synthesis and transport from SCs at the graft site for ensuring local immune tolerance. Our results also establish a new paradigm for creating tolerable grafts for other chronic diseases such as diabetes, anemia, and central nervous system (CNS) diseases, and advance the science of graft tolerance.